Abstract
BackgroundExploring the molecular mechanisms underlying directed differentiation is helpful in the development of clinical applications of mesenchymal stem cells (MSCs). Our previous study on dental tissue-derived MSCs demonstrated that secreted frizzled-related protein 2 (SFRP2), a Wnt inhibitor, could enhance osteogenic differentiation in stem cells from the apical papilla (SCAPs). However, how SFRP2 promotes osteogenic differentiation of dental tissue-derived MSCs remains unclear. In this study, we used SCAPs to investigate the underlying mechanisms.MethodsSCAPs were isolated from the apical papilla of immature third molars. Western blot and real-time RT-PCR were applied to detect the expression of β-catenin and Wnt target genes. Alizarin Red staining, quantitative calcium analysis, transwell cultures and in vivo transplantation experiments were used to study the osteogenic differentiation potential of SCAPs.ResultsSFRP2 inhibited canonical Wnt signaling by enhancing phosphorylation and decreasing the expression of nuclear β-catenin in vitro and in vivo. In addition, the target genes of the Wnt signaling pathway, AXIN2 (axin-related protein 2) and MMP7 (matrix metalloproteinase-7), were downregulated by SFRP2. WNT1 inhibited the osteogenic differentiation potential of SCAPs. SFRP2 could rescue this WNT1-impaired osteogenic differentiation potential.ConclusionsThe results suggest that SFRP2 could bind to locally present Wnt ligands and alter the balance of intracellular Wnt signaling to antagonize the canonical Wnt pathway in SCAPs. This elucidates the molecular mechanism underlying the SFRP2-mediated directed differentiation of SCAPs and indicates potential target genes for improving dental tissue regeneration.
Highlights
Exploring the molecular mechanisms underlying directed differentiation is helpful in the development of clinical applications of mesenchymal stem cells (MSCs)
The results showed that overexpression of secreted frizzled-related protein 2 (SFRP2) increased the expression of p-β-catenin and p-GSK-3β in Stem cells from apical papilla (SCAPs) (Fig. 1b and c)
Overexpression of SFRP2 did not affect the expression of WNT5a, which is a representative of the non-canonical wnt signaling pathway (Additional file 1: Fig. S1)
Summary
Exploring the molecular mechanisms underlying directed differentiation is helpful in the development of clinical applications of mesenchymal stem cells (MSCs). Displaying the potential to differentiate into various cell types, including odontoblasts, osteoblasts, chondrocytes, myocytes and adipocytes, these cells are capable of self-renewal, are accessible and more intimately associated with dental tissues, can generate bone- or dentin-like mineralized tissues, and can repair tooth defects [1,2,3,4,5]. Their potential clinical applications are limited because the mechanism underlying their directed differentiation remains largely unknown. Delicate control of Wnt signaling is crucial for hemostasis and tissue regeneration
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